Interstitial cystitis/painful bladder syndrome (IC) is a devastating condition characterized by severe pelvic pain and voiding dysfunction. Despite years of investigation, no etiology or widely effective therapies exist for IC, indicating the needto consider new ideas and approaches. Based on several lines of evidence, the "microbiome" is an emerging field of study that has the potential to play a significant role in our understanding of I. First, many IC patients exhibit Gl or reproductive tract co-morbidities. Second, it is established that crosstalk exists among the bladder, Gl tract, and reproductive tract. Third, we find that bacteria can mediate a range of pelvic pain responses, from pain suppression to causing chronic pain. Fourth, microbial flora densely populate certain body sites, indeed outnumbering human cells, and new findings demonstrate that altered microbiomes can drive complex diseases. We therefore will develop an interdisciplinary team to address this novel question: is an altered gastrointestinal and/or reproductive tract microbiome associated with IC? Our team will bring together clinical expertise in IC, methodologic and biologic expertise in defining microbiomes of the Gl and reproductive tracts, and expertise in the microbial basis of pelvic pain. Our team will exploit the synergies from these key fields to develop specific hypotheses and strategies for defining associations between microbiomes and IC. Moreover, clinically relevant murine models will be developed to establish a causal link between altered microbiomes and modulation of pelvic pain. Defining IC microbiomes has potentially major significance for understanding IC etiology, mechanisms, and treatments. IC patients often have a history of antibiotic treatments for urinary tract infection, yet antibiotics can shift microbial diversity and thereby cause disease. Altered IC microbiomes could result in dysfunctional modulation of pelvic pain via organ crosstalk or expanded reservoirs of uropathogens. Finally, manipulation of microbiomes is proving efficacious in other clinical specialties, suggesting the possibility of possibility of convenient probiotic therapies for IC. PUBLIC HEALTH RELEVANCE: Interstitial cystitis/painful bladder syndrome (IC) is a debilitating chronic bladder condition without known cause or effective treatments. This study will develop an interdisciplinary team to explore the novel question of whether alterations in the large bacterial communities that populate the gastrointestinal and reproductive tracts play a causal role in IC.